CN106442990A - System for predicting prognosis of patient with lung squamous cell carcinoma - Google Patents
System for predicting prognosis of patient with lung squamous cell carcinoma Download PDFInfo
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Abstract
The invention discloses a system for predicting the prognosis of a patient with lung squamous cell carcinoma. The system includes a subsystem for detecting the expression quantity of such five proteins as EGFR, p38alpha, AKT1, SOX2 and E-cadherin and a protein expression quantity data processing system. The subsystem for detecting the expression quantity of the five proteins is allowed to measure the expression quantity of the proteins through an immunohistochemistry staining method; the protein expression quantity data processing system is allowed to convert the expression quantity of the five proteins from the squamous cell carcinoma tissues separated from the patient with the lung squamous cell carcinoma to a prognostic score; based on the prognostic score, the prognosis of a patient with the lung squamous cell carcinoma is predicted.
Description
Technical field
The present invention relates to biomedical sector is and in particular to be used for predicting the system of Lung Squamous Carcinoma Patients prognosis.
Background technology
Pulmonary carcinoma is modal reason in cancer related mortality in the world today, and wherein 80% is nonsmall-cell lung cancer
(NSCLC).TNM stage is at present for the generally accepted different clinical staging systems of people, is used for predicting prognosis and referring to
Lead the treatment of Patients with Non-small-cell Lung.However, current TNM stage system is far not enough to Accurate Prediction non-small cell
The prognosis situation of patients with lung cancer.Such as, for patients with lung cancer, even at clinical-stage, the relapse rate of pulmonary carcinoma
Also it is up to 35-50%.In addition, quite a few patient only can cure by modus operandi, these patients should keep away
Exempt from based on current TNM system and carry out the extremely strong side reaction that adjuvant chemotherapy is brought.
In order to improve the prediction effect to Patients with Non-small-cell Lung prognosis, people have had been put into very big effort and have gone to identify
The molecular marker related with identifying it is composed.The team of a lot of research pulmonary carcinoma all once reported there is different prognosis ability
Gene expression profile.However, up to the present going back neither one gene expression profile to be applied to nonsmall-cell lung cancer clinical prognosis
Prediction.
Lung squamous cancer, also known as lung squamous cell cancer, accounts for the 40%～51% of primary lung cancer, is more common in middle-aging male,
There is substantial connection with smoking.Mainly by being formed after bronchial mucosa columnar epithelial cell metaplasia, including in bronchus
Chrotoplast is subject to chronic stimulation and damage, cilium forfeiture, basal cell squamous metaplasia or typical hypertrophy etc..Lung squamous cancer with
Centre type pulmonary carcinoma is common, and has the tendency of ductus thoracicus Intracavity, and lung squamous cancer early stage often causes bronchial stenosises, or obstructive
Pneumonia.The grade malignancy variation of lung squamous cancer is larger, and in general compared with other several pulmonary carcinoma, scale cancer growth is more slow
Slowly, often find when tumor grown larger.
Content of the invention
The technical problem to be solved is how to carry out prognosis prediction to Lung Squamous Carcinoma Patients.
For solving above-mentioned technical problem, present invention firstly provides being used for predicting the system of Lung Squamous Carcinoma Patients prognosis, including
Detection EGFR, p 38 alpha, the system of this five kinds of protein expressions of AKT1, SOX2 and E-cadherin.
In the above-mentioned system for predicting Lung Squamous Carcinoma Patients prognosis, described detection EGFR, p 38 alpha, AKT1, SOX2 and
The system of this five kinds of protein expressions of E-cadherin may include described by Cell immunohistochemical staining method mensure
Reagent needed for the expression of five kinds of protein and/or instrument.
In the above-mentioned system for predicting Lung Squamous Carcinoma Patients prognosis, the described system bag for predicting Lung Squamous Carcinoma Patients prognosis
Include including protein expression amount data handling system, described protein expression amount data handling system is used for will be pre- from treating
Survey five kinds of protein expressions described in the detached lung squamous cell carcinoma cancers (lung squamous cell carcinoma cancers of excision) of Lung Squamous Carcinoma Patients
Amount is converted to the prognosis score value of described Lung Squamous Carcinoma Patients to be predicted, according to the prognosis score value of described Lung Squamous Carcinoma Patients to be predicted
Predict the prognosis of described Lung Squamous Carcinoma Patients to be predicted.
In the above-mentioned system for predicting Lung Squamous Carcinoma Patients prognosis, in described protein expression amount data handling system, set mould
Block 1-a and module 1-b, described module 1-a is used for the detached lung squamous cell carcinoma cancers from Lung Squamous Carcinoma Patients to be predicted
Described in five kinds of protein expressions be converted to the prognosis score value of described Lung Squamous Carcinoma Patients to be predicted, described module 1-b is used
Predict the prognosis of described Lung Squamous Carcinoma Patients to be predicted in the prognosis score value according to described Lung Squamous Carcinoma Patients to be predicted.
Described detection EGFR, p 38 alpha, the system of this five kinds of protein expressions of AKT1, SOX2 and E-cadherin exist
Application in the system of preparation prediction Lung Squamous Carcinoma Patients prognosis falls within protection scope of the present invention.
Described detection EGFR, p 38 alpha, the system of this five kinds of protein expressions of AKT1, SOX2 and E-cadherin and
Application in the system of preparation prediction Lung Squamous Carcinoma Patients prognosis for the protein expression amount data handling system falls within the present invention
Protection domain；Described protein expression amount data handling system is any of the above-described described protein expression amount data processing
System.
In above-mentioned application, described detection EGFR, p 38 alpha, this five kinds of protein tables of AKT1, SOX2 and E-cadherin
The system of the amount of reaching may include the examination measuring needed for the expression of described five kinds of protein by Cell immunohistochemical staining method
Agent and/or instrument.
In the above-mentioned system for predicting Lung Squamous Carcinoma Patients prognosis, described five kinds of protein are both from people (Homo
sapiens).
In the above-mentioned system for predicting Lung Squamous Carcinoma Patients prognosis, described Lung Squamous Carcinoma Patients excise lung squamous cancer group for underwent operative
The Lung Squamous Carcinoma Patients knitted.
In the above-mentioned system for predicting Lung Squamous Carcinoma Patients prognosis, detect the system tool of the expression of above-mentioned five kinds of protein
Body can be the reagent needed for the expression of the Cell immunohistochemical staining method above-mentioned five kinds of protein of mensure and/or instrument, such as
The monoclonal antibody of EGFR or the monoclonal of polyclonal antibody, the monoclonal antibody of p 38 alpha or polyclonal antibody, AKT1
The monoclonal antibody of antibody or polyclonal antibody, the monoclonal antibody of SOX2 or polyclonal antibody and E-cadherin or
Polyclonal antibody.
For solving above-mentioned technical problem, present invention also offers a kind of method of prediction Lung Squamous Carcinoma Patients prognosis.
The method of prediction Lung Squamous Carcinoma Patients prognosis provided by the present invention, including：C, detection are derived from lung squamous cancer to be predicted
The EGFR of detached lung squamous cell carcinoma cancers sample of patient, p 38 alpha, this five kinds of albumen of AKT1, SOX2 and E-cadherin
Matter expression；D, described five kinds of protein expressions are converted to the prognosis score value of described Lung Squamous Carcinoma Patients to be predicted, root
Prognosis score value according to described Lung Squamous Carcinoma Patients to be predicted predicts the prognosis of described Lung Squamous Carcinoma Patients to be predicted.
In said method, prognosis score value can also be (soft by " screening of combination molecule mark and model build software "
Part copyright registration number is 2014SR142190) obtain.
In said method, described five kinds of protein expressions can obtain according to Cell immunohistochemical staining method.
In said method, described detached lung squamous cell carcinoma cancers sample may be from the detached of described Lung Squamous Carcinoma Patients to be predicted
Sample that lung squamous cell carcinoma cancers are prepared through formalin fix paraffin embedding or from described Lung Squamous Carcinoma Patients to be predicted point
From lung squamous cell carcinoma cancers frozen section.
In said method, described five kinds of protein expressions are converted to the prognosis score value of described Lung Squamous Carcinoma Patients to be predicted
Method may include and described five kinds of protein expressions is converted into protein expression amount vector, by described protein expression amount
Vector substitutes into formula 1 and obtains f (v), and f (v) is substituted into formula 2, and the prognosis obtaining described Lung Squamous Carcinoma Patients to be predicted divides
Value；
Described formula 1 is：
In described formula 1, v is protein expression amount vector, referred to as vector, and sv_coef (i) is the coefficient of supporting vector,
SV (i) is supporting vector；
Described formula 2 is：
In described formula 2, prob (v) is the prognosis score value of Lung Squamous Carcinoma Patients to be predicted.
Described protein expression amount vector is represented with v, v=(xAKT1,xE-cadherin,xEGFR,xp38α,xSOX2).
In said method, the prognosis score value according to described Lung Squamous Carcinoma Patients to be predicted predicts described Lung Squamous Carcinoma Patients to be predicted
Prognosis can be that diagnostic threshold is determined by Receiver operating curve's (ROC curve), relatively described lung to be predicted
The prognosis score value of squamous cell carcinoma patients and the size of described diagnostic threshold, if the prognosis score value of described Lung Squamous Carcinoma Patients to be predicted
Less than or equal to described diagnostic threshold, the prognosis malas of described Lung Squamous Carcinoma Patients to be predicted, if described lung squama to be predicted
The prognosis score value of cancer patient is more than described diagnostic threshold, the prognosis bona of described Lung Squamous Carcinoma Patients to be predicted.
Index for diagnosis also can (software copyright registration number be by " nonsmall-cell lung cancer Index for diagnosis software "
2014SR157070) obtain.
Described determine that diagnostic threshold is the normal lung with statistical significance quantity by Receiver operating curve
Five kinds of protein expressions described in tissue are comparison, according to having described in the lung squamous cell carcinoma cancers of statistical significance quantity
Five kinds of protein expressions and corresponding Lung Squamous Carcinoma Patients grouping information make Receiver operating curve, ROC curve
On optimal value be threshold value；Described grouping information is Lung Squamous Carcinoma Patients when excision lung squamous cell carcinoma cancers start survival
Between, (more than or equal to 3 years) is one group within more than 3 years, is one group less than 3 years (less than 3 years)；Described optimal value
It is that sensitivity is as large as possible on the basis of specificity maximum.
For solving above-mentioned technical problem, present invention also offers D1) and/or D2) in application：
D1) EGFR, p 38 alpha, five kinds of protein of AKT1, SOX2 and E-cadherin are predicting lung squama as mark
Application in cancer patient's prognosis；
D2) EGFR, p 38 alpha, five kinds of protein of AKT1, SOX2 and E-cadherin are predicted in preparation as mark
Application in the product of Lung Squamous Carcinoma Patients prognosis.
Present invention also offers a kind of method producing lung squamous cancer related protein characteristic spectrum, it is derived from TNM including detection
EGFR, p 38 alpha, AKT1, SOX2 and E-cadherin in the detached lung squamous cell carcinoma cancers sample of I-III phase Lung Squamous Carcinoma Patients
The step of five kinds of protein expressions.
Lung Squamous Carcinoma Patients described herein can be TNM I-III phase Lung Squamous Carcinoma Patients.Further, described herein
Lung Squamous Carcinoma Patients concretely TNM IB-IIIA phase Lung Squamous Carcinoma Patients.
Prognosis malas described herein are to start the time-to-live less than 3 years from the excision lung squamous cell carcinoma cancers time, institute
Stating prognosis bona is to start the time-to-live for 3 years and more than 3 years from the excision lung squamous cell carcinoma cancers time.
The detached lung squamous cell carcinoma cancers of Lung Squamous Carcinoma Patients to be predicted described herein can be the lung squamous cancer group of excision
Knit.
EGFR described herein is receptor tyrosine protein kinase ErbB-1 in the record name (RecName) of NCBI
(Receptor Tyrosine-Protein Kinase ErbB-1)；Described p 38 alpha is in the record name of NCBI
(RecName) it is mitogen-activated protein kinase 14 (Mitogen-activated protein kinase 14)；
Described AKT1 NCBI record name (RecName) be V-Akt mouse thymus tumor virus oncogene homology 1
(V-Akt Murine Thymoma Viral Oncogene Homolog 1)；Described SOX2 is in the record name of NCBI
(RecName) it is sex-determining region Y's frame albumen 2 (SRY (Sex Determining Region Y)-Box 2)；
Described E-cadherin is 1 type cadherin (Cadherin 1, Type in the record name (RecName) of NCBI
1,E-Cadherin(Epithelial)).
In the present invention, in lung tumor tissue samples, The People's Hospital of Peking University has 88 squamous cell carcinoma patients cases to meet sample to enter
Select standard, as Beijing scale cancer sample cluster, Beijing scale cancer sample cluster is named as BJ scale cancer group.In BJ scale cancer
In group, the sample (58) of random selection 2/3rds is as scale cancer training group, another 1/3rd sample (30)
As scale cancer test group.In lung tumor tissue samples, Xinan Hospital, Chongqing has 82 squamous cell carcinoma patients cases to meet sample and is selected in
Standard, as Chongqing individual authentication scale cancer sample cluster, Chongqing individual authentication scale cancer sample cluster is named as CQ scale cancer
Group.By the micro-array tissue (TMA) of scale cancer training group sample is carried out with SABC (IHC) dyeing, Wo Menfen
Analyse the expression of 75 signal-proteins playing a crucial role during tumor development.By random forest
Algorithm and the combination of algorithm of support vector machine, have obtained the characteristic spectrum of lung squamous cancer (ADC) related protein and have developed point
Class model, i.e. 5- protein model.Then scale cancer test group sample and CQ scale cancer group are used to P5-ADC prognosis scale cancer side
Method is verified further.
Result shows, the P5-ADC being made up of five protein EGFR, p 38 alpha, AKT1, SOX2 and E-cadherin
Complete protein is the protein characteristic spectrum of Accurate Prediction lung squamous cancer.In scale cancer test group, prognosis bona organizes patient's
Survival rate is 72.7% (confidence interval is 37.1%-90.3%) within 3 years, and 3 years survival rates of prognosis malas group patient are
16.7% (confidence interval is 4.1%-36.5%), between prognosis bona's group and prognosis malas group, Hazard ratio is 7.67 (confidence areas
Between be 3.96-39.34)；In CQ scale cancer group, 3 years survival rates that prognosis bona organizes patient are 97.6% (confidence interval
For 83.6%-99.7%), and 3 years survival rates of prognosis malas group patient are that 29.3% (confidence interval is
16.4%-43.4%), between two groups, Hazard ratio is 2.81 (confidence interval is 1.65-6.05).Cox regression analyses show,
The efficiency of the characteristic spectrum of scale cancer related protein is better than TNM hierarchy system can be used as independent prognostic factor.
Result it is also shown that P5-ADC prognosis scale cancer method provided by the present invention can Accurate Prediction lung squamous cancer clinical prognosis
Situation, significantly improves the prognosis prediction level of Lung Squamous Carcinoma Patients；P5-ADC prognosis scale cancer method is also to TMN classification
The further prognosis of squamous cell carcinoma patients.
Brief description
Fig. 1 is establishment and the efficiency checking of P5-ADC prognosis scale cancer method.
Wherein A is the ROC curve of scale cancer training group；B is the prognosis of scale cancer training group；C is the prognosis of scale cancer test group；
D is the distribution of prognosis score value, prognosis prediction result, scale cancer characteristic spectrum and patient's reagent survival condition total figure of BJ scale cancer group；
E is the prognosis of CQ scale cancer group；F is the prognosis score value distribution of CQ scale cancer group, prognosis prediction result, scale cancer characteristic spectrum and
Patient's reagent survival condition total figure.
Fig. 2 is the prognosis to the squamous cell carcinoma patients that clinical TMN is classified for the P5-ADC prognosis scale cancer method.
Wherein A is the prognosis of TMN I B phase squamous cell carcinoma patients；B is the prognosis of TMN II phase squamous cell carcinoma patients；C is TMN III
The prognosis of A phase squamous cell carcinoma patients.
Specific embodiment
Experimental technique used in following embodiments if no special instructions, is conventional method.
Material used, reagent etc. in following embodiments, if no special instructions, all commercially obtain.
Involved explanation of nouns in following embodiments：
Prognosis bona：From ocal resection when, the survival of patients time was more than 3 years.
Prognosis malas：From ocal resection when, patient is dead in 3 years.
Overall survival (OS)：From accept death that pulmonary carcinoma radical-ability surgical operation causes to any reason or the last time with
Time period between visit.
Overall survival：Survival rate during one colony's particular point in time.
Receiver operating curve (receiver operating characteristic curve, abbreviation ROC
Curve)：It is according to a series of different two mode classifications (cut off value or decision threshold), with sensitivity (True Positive Rate)
The curve drawn for abscissa for vertical coordinate, 1- specificity (true negative rate).Under ROC curve, area is important
Experimental accuracy index, under ROC curve, area is bigger, and the diagnostic value of test is bigger.
Sensitivity (True Positive Rate)：Actual ill and be correctly judged as ill percentage rate by test standard, spirit
Sensitivity is the bigger the better, and ideal sensitivity is 100%.
1- specificity (true negative rate)：It is actual anosis and be correctly judged as anosis percentage rate by test standard,
Specificity is the bigger the better, and preferable specificity is 100%.
Embodiment 1, the discovery of scale cancer related protein characteristic spectrum, combination molecule mark model, nonsmall-cell lung cancer
The checking of Index for diagnosis, P5-ADC prognosis scale cancer method and effectiveness
1st, the discovery of scale cancer related protein characteristic spectrum
1.1st, case and sample
Described formalin fix and paraffin-embedded people normal lung tissue sample, by The People's Hospital of Peking University and southwest
Hospital organization storehouse provides.Described formalin fix and paraffin-embedded lung tumor tissue samples, by the Peking University people
The tissue bank of hospital pathology department and Xinan Hospital, Chongqing Pathology Deparment provides.The supplier (i.e. patient) of lung tumor tissue exists
Pulmonary carcinoma radical-ability surgical operation systematic is received in above-mentioned hospital during 2004 to 2010.The present invention is not
Case including situations below：The case previously having malignant tumor, the case accepting the treatment of other means before surgery,
Operation not exclusively the case of excision, accepted epidermal growth factor (EGFR) treatment with tyrosine kinase inhibitors case,
The case of small cell lung cancer, exist by the wellability precancerous lesion of IASLC (IASIC) standard definition
Case and dead case in those postoperative 30 days.The histopathology being adopted according to World Health Organization (WHO) (WTO)
Categorizing system, the pathological section that all cases dye through hematoxylin-eosin (H＆E), all carry out again concentrating examining,
And confirm tumor type, histological grade and neoplasm metastasis degree.Clinical and follow-up information comes from the prediction of hospital
Property case database.
In lung tumor tissue samples, The People's Hospital of Peking University has 88 squamous cell carcinoma patients cases to meet sample inclusion criteria, will
It, as Beijing scale cancer sample cluster, Beijing scale cancer sample cluster is named as BJ scale cancer group.BJ scale cancer group selects at random
Select 2/3rds sample (58) as scale cancer training group, another 1/3rd sample (30) is surveyed as scale cancer
Examination group.In lung tumor tissue samples, Xinan Hospital, Chongqing has 82 squamous cell carcinoma patients cases to meet sample inclusion criteria, by it
As Chongqing individual authentication scale cancer sample cluster, Chongqing individual authentication scale cancer sample cluster is named as CQ scale cancer group.
1.2nd, prepare organization chip
The paraffin embedding lung tumor tissue samples of scale cancer training group are cut into slices one by one, morphological observation is done in H＆E dyeing,
The exemplary position of pathological changes is marked as point of puncture, then uses trepan device Puncture Lung tumor tissues wax stone (diameter
2 millimeters) obtain lung tumor tissue wax core.
Paraffin-embedded people normal lung tissue sample is cut into slices, H＆E dye marker goes out as point of puncture, then uses ring
Boring device punctures normal lung tissue's wax stone (2 millimeters of diameter) and obtains normal lung tissue's wax core.
Above-mentioned lung tumor is organized wax core and normal lung tissue's wax core to match one by one, is transferred to row in the array of acceptor wax block
Row, obtain organization chip.
Each acceptor wax block comprises an organization chip, and every organization chip comprises 30 scale cancer cases.
1.3rd, immunohistochemical staining and chemical score
The organization chip of above-mentioned 1.2 preparations is carried out immunohistochemical staining, concretely comprises the following steps：A：Dry piece, dewax and wash
Piece：Tissue array wax stone is continuously cut into 4 micrometer thick sections and is fixed on microscope slide, microscope slide through 2 hours 60 DEG C
After baking, soaked in order successively, dewaxed by dimethylbenzene, graded ethanol and water, PBS (pH7.4) is developed a film 3
Secondary, each 3min；B：Antigen recovery：By section, 95 DEG C carry out antigen retrieval 15min；C：Add 3% hydrogen peroxide
Room temperature treatment 30min blocks endogenous peroxidase activity；D：10% Normal Goat Serum is added to close non-specific egg
White matter, section is at 4 DEG C with 75 kinds of antibody incubations overnight；E：According to ABC test kit (Vector Laboratories company
Product) step carries out enhancement process, addition two is anti-and DAB develops the color；F：Brazilwood extract dyeing, cutting sheet flushing is totally simultaneously
Mounting.The partial antibody using during immunohistochemical analysis is：Antibody (rabbit source monoclonal antibody, the sale company of anti-EGFR
Epitomics, production number #1902-1), the antibody of anti-p 38 alpha (rabbit source multi-resistance, sell company Santa Cruz, product
Article Number SC-535), the antibody of anti-AKT1 (rabbit source monoclonal antibody, sell company Epitomics, production number #1085-1),
The antibody (rabbit source monoclonal antibody, sale company Epitomics, production number #2696-1) of anti-SOX2 and anti-E-cadherin
Antibody (Mus source monoclonal antibody, sell company BD, production number 610182).
Immunohistochemical staining evaluation adopts modified form immunohistochemistry scoring (histopathology dyeing scoring) system to carry out.
This system is estimated by quantitatively assigning after dividing to the staining power of pathological section and the percentage ratio of positive cell, wherein
May be defined as 0 point, 1 point, 2 points, 3 points according to staining power, correspond respectively to negative staining, weakly stained sun, dye
Color middle-jiao yang, function of the spleen and stomach and dyeing sun by force；Meanwhile, count the percentage ratio of each intensity positive cell.All of immunohistochemical staining is cut
Piece is all through 3 professional pathologist's evaluated in parallel, and does not know about the clinical information of patient in advance.If 3 pathology
Family disagrees to the deciphering of section, and 3 pathologists will reappraise to this section, together until reaching common understanding.Change
Learning score calculation formula is：Every kind of protein expression score value=1 × weakly positive percentage rate+2 × positives percentage rate+3 × strong
Positive percentage.
1.4th, the data processing of protein expression profile
The data processing of protein characteristic spectrum：Method according to above-mentioned 1.3 assesses each protein expression score value one by one,
Score value normalized first will be expressed, missing values are substituted by the intermediate value of this protein expression in all tumors, then
Calculate the score value of each protein and the expression ratio of this protein meansigma methods of scale cancer training group, afterwards expression with
The log of expression ratio10(expression ratio) quantifies.In order to avoid in logarithm 0 appearance, all fractions all add 0.01.
1.5th, the characteristic spectrum of scale cancer related protein
Scale cancer training group application random forests algorithm is obtained the importance index of each protein.Using the outer data of bag
[out-of-bag (OOB)] error minimize criterion, cuts down the most unessential protein successively, less OOB error
If the dried protein i.e. characteristic spectrum as lung squamous cancer related protein.Said process is by random forest software kit
Realized using R varSelRF bag program.
Support vector machine (SVM) are used to develop the disaggregated model of the training group with characteristic spectrum.Select RBF
(RBF) kernel carries out SVM training, because when non-linear between category feature spectrum and attribute, by nonlinear mapping sample
To higher dimensional space, kernel can process these situations to product.Two parameters C of RBF kernel and γ can use grid
Search strategy is tuned.The optimum C and γ training through SVM for the disaggregated model forms.In training stage, the property of SVM
Can be estimated by 5 times of cross validation precision.
1.6th, statistical analysiss
Because the cause of the death of patient is difficult to entirely accurate definition, it is used specific existence point may bring as existence terminal latent
Deviateing, therefore we are using total existence of starting from the ocal resection time as our main analysis events.With
Kaplan-Meier analyzes overall patient's survival rate.With bilateral logarithm order (two-sided log-rank) check analyses
The efficiency of the life span of prognosis bona patient, the life span of prognosis malas patient and adjuvant chemotherapy.Related change
Amount is big including the characteristic spectrum determination of scale cancer related protein, patient age, cigarette smoking index, histological type, tumor
Little and disease stage etc., is all compared by the result of single argument and multivariate Cox proportional hazards analysis.Wald is seemingly
So it is applied to check single argument and multivariate analyses than (Wald likelihood ratio) inspection, to assess whether to have
Statistically significant.More whether Cox proportional hazards analysis and bilateral Log-Rank Test are also used for accepting complementary simultaneously
Overall survival between the patient of chemotherapy.All of statistical test, is considered as there is system with default bilateral α less than 0.05
Meaning learned by meter.Above-mentioned analysis is all to complete under R programming language (3.0.2 version).
According to above-mentioned 1.1 1.6 method, the present invention, with scale cancer training group as sample, occurs to send out by detection and tumor
The expression opening up 75 closely related signal-proteins finds the characteristic spectrum of lung squamous cancer related protein.Lung squamous cancer phase
The characteristic spectrum closing protein includes five kinds of protein, and the title of five kinds of protein is respectively EGFR, p 38 alpha, AKT1, SOX2
And E-cadherin.The characteristic spectrum of lung squamous cancer related protein hereinafter referred to as scale cancer characteristic spectrum.By this five kinds of protein
EGFR, p 38 alpha, the complete protein of AKT1, SOX2 and E-cadherin composition are named as P5-ADC.
2nd, combination molecule mark model and nonsmall-cell lung cancer Index for diagnosis
2.1st, combination molecule mark model
The lung squamous cancer characteristic spectrum that will be seen that adopts algorithm of support vector machine to develop disaggregated model, and this model full name is combination point
Sub- mark model, referred to as 5- protein model.Again the Prognostic scoring system of each patient is calculated, prognosis score value
Represent the integrated information of each protein in 5- protein model.
Above-mentioned 5- protein model can clearly be applied to clinic with very simple.The using method of 5- protein model
For：(1) the method using SABC for each Lung Squamous Carcinoma Patients detects the expression score value of 5 marker proteins；
(2) the expression of 5 protein molecules is normalized using following equation：
fs(x)=- 1+2 (x-lower)/(upper-lower)；
In formula, x is the expression of protein molecule after quality control standard, the corresponding Upper of each protein (on
Limit) and Lower (lower limit) list in Table 1；
Table 1. scale cancer marker protein molecule normalization coefficient
| Protein | Lower | Upper |
| AKT1 | -1.131249036 | 0.211173644 |
| E-cadherin | -0.791163384 | 0.178873393 |
| EGFR | -1.212120146 | 0.250277851 |
| p38α | -0.970134933 | 0.352084361 |
| SOX2 | -0.650762327 | 0.639272285 |
(3), after obtaining the normalized expression of 5 protein molecules, each patient can be expressed as by this 5 protein
Molecular protein molecule vector v：V=(xAKT1,xE-cadherin,xEGFR,xp38α,xSOX2).
(4) patient's protein molecule vector v is substituted into following equation and calculate f (v)：
Wherein, sv_coef (i) is the coefficient of supporting vector, and SV (i) is supporting vector (table 2)；
Supporting vector in table 2. combination molecule mark model and coefficient
(5) f (v) substitution following equation is calculated the prognosis score value of this patient：
2.2nd, nonsmall-cell lung cancer Index for diagnosis
The acquisition of threshold value：The performance of scale cancer characteristic spectrum is by receiver-operating characteristic (ROC)
Analysis is estimated.The expression score value of the P5-ADC with normal lung tissue is comparison, according to each trouble of scale cancer training group
(grouping information refers to that patient started to deposit from the excision time to the grouping information of the expression score value of the P5-ADC of person and patient
The time lived, it is one group within more than 3 years, be one group within less than 3 years；It is shown in Table 3) carry out ROC with SPSS 16.0 software
Tracing analysiss.Area (AUC) under scale cancer training group scale cancer characteristic spectrum ROC curve is 0.913, shows to instruct in scale cancer
Practice this scale cancer characteristic spectrum in group can accurately prognosis be predicted (A in Fig. 1).Optimal value on ROC curve is
For threshold value, consider Sensitivity and Specificity, refer to that sensitivity is as large as possible on the basis of specificity maximum.
Based on this method, the optimal value of scale cancer training group ROC curve is 0.597, and that is, threshold value is 0.597.In scale cancer training
On this node of group, lung squamous cancer characteristic spectrum shows 75.8% sensitivity and 96.0% 1- specificity, 96.2%
In positive predictive value and patient 3 years, dead overall accuracy is 84.5%.
The expression score value of table 3. scale cancer training group lung squamous cancer related protein and grouping information
| No. | Life span (moon) | AKT1 | E-cadherin | EGFR | p38α | SOX2 |
| 1 | 9.53 | 1.75 | 1.7 | 2.3 | 1.25 | 0 |
| 2 | 3.80 | 0 | 0.2 | 0.15 | 0.35 | 0 |
| 3 | 114.93 | 0 | NA | 0 | NA | 0 |
| 4 | 84.33 | 0.35 | 1.65 | 0 | 1.25 | 0 |
| 5 | 110.13 | 0.8 | 2.2 | 0.1 | 0.6 | 1.65 |
| 6 | 109.00 | 0 | 2.25 | 1.25 | 0.85 | 1.4 |
| 7 | 106.87 | 1.3 | 2.4 | 1.75 | 1.95 | 0 |
| 8 | 106.20 | 1.7 | 2.2 | 1.6 | 1.85 | 1.85 |
| 9 | 5.60 | 1.85 | 2.3 | 2.4 | 1.6 | 0 |
| 10 | 105.80 | 0 | NA | 1.45 | 1.3 | 0 |
| 11 | 16.23 | 1.5 | 2.5 | 2.4 | 1.3 | 0 |
| 12 | 21.50 | 1.95 | 1.85 | 2.1 | 0.3 | 0 |
| 13 | 103.17 | 1.4 | 2.45 | 1.6 | 1.85 | 0 |
| 14 | 103.13 | 1.35 | 2.4 | 1.6 | 0.9 | 1.8 |
| 15 | 17.23 | 1.8 | 2.25 | 2.1 | 0.65 | 0.35 |
| 16 | 101.50 | 1.35 | NA | 1.3 | 1.4 | 0 |
| 17 | 7.73 | 1.5 | 1.65 | 1.4 | 0.95 | 0 |
| 18 | 75.10 | 1.35 | 1.5 | 1.75 | 0.7 | 0 |
| 19 | 92.77 | 0.6 | 1.4 | 1.3 | 0.2 | 0 |
| 20 | 59.53 | 1.1 | 2.2 | 0 | 0.65 | 0.45 |
| 21 | 4.33 | 1.4 | 1.65 | 1.35 | 1.35 | 0 |
| 22 | 13.33 | 1.3 | 1.8 | 2.7 | 1 | 0.1 |
| 23 | 86.17 | 1.2 | 1.5 | 1.3 | 2 | 0 |
| 24 | 85.63 | 1.9 | 1.85 | 0.4 | 1.75 | 0 |
| 25 | 58.33 | 1.05 | 2.2 | 2 | 0.6 | 0 |
| 26 | 81.80 | 1.1 | 1.9 | 1.75 | 1.2 | 0 |
| 27 | 80.40 | 1.2 | 1.55 | 1.7 | 1.8 | 1.15 |
| 28 | 79.57 | 2 | 2.6 | 1.75 | 1.9 | 0 |
| 29 | 79.50 | 1.95 | 2.55 | 1.4 | 0.8 | 0.5 |
| 30 | 78.77 | 1.15 | 1.6 | 2.75 | 1.3 | 0.4 |
| 31 | 31.80 | 0.65 | 0.4 | 0.15 | 0.35 | 0 |
| 32 | 78.27 | 1.65 | 2.25 | 1.55 | 1.3 | 0.2 |
| 33 | 75.23 | 0.7 | 1.45 | 2.8 | 0.15 | 0 |
| 34 | 3.93 | 0.65 | 2.2 | 1.4 | 0.9 | 0 |
| 35 | 20.03 | 0.4 | 1.5 | 1.75 | 0.7 | 0.1 |
| 36 | 71.40 | 1.65 | 1.9 | 1.95 | 1.8 | 0.65 |
| 37 | 71.17 | 2.05 | 2.6 | 1.7 | 1 | 1.65 |
| 38 | 2.27 | 0.3 | 1.9 | 1.85 | 1.2 | 0 |
| 39 | 3.43 | 1.9 | 0.4 | 1.75 | 1.2 | 0 |
| 40 | 42.60 | 1.25 | 2.55 | 1.25 | 0.85 | 0 |
| 41 | 58.03 | 1.6 | 1.65 | 1.6 | 1.6 | 0 |
| 42 | 62.83 | 1.6 | 2.3 | 1.65 | 1.1 | 0 |
| 43 | 40.03 | 1.15 | 0.7 | 1.2 | 1.1 | 0.4 |
| 44 | 61.67 | 1.75 | 2.7 | 1.1 | 1.3 | 0.8 |
| 45 | 32.27 | 0.7 | 1.65 | 2.3 | 0.4 | 0 |
| 46 | 59.53 | 1.5 | 2.25 | 1.55 | 0.85 | 0 |
| 47 | 58.03 | 2.1 | 2.6 | 1.85 | 1.4 | 1.75 |
| 48 | 11.73 | 0 | 0.25 | 2.2 | 0.1 | 0 |
| 49 | 57.10 | 1.75 | 1.6 | 1.65 | 0.35 | 0.1 |
| 50 | 6.23 | 0.75 | 1.65 | 1.8 | 0.55 | 0 |
| 51 | 30.30 | 1.55 | 1.45 | 2.4 | 1.65 | 0 |
| 52 | 15.20 | 0.3 | 1.85 | 0.5 | 0 | 0.65 |
| 53 | 11.57 | 0.6 | 1.8 | 1.8 | 0.9 | 0.15 |
| 54 | 14.17 | 0.3 | 2.3 | 2 | 0.7 | 0 |
| 55 | 16.60 | 0.55 | 0.7 | 1.4 | 0.5 | 0 |
| 56 | 19.00 | 0 | 1.6 | 1.65 | 0.1 | 0.25 |
| 57 | 9.47 | 2 | 1.9 | 1.05 | 0.2 | 0.85 |
| 58 | 9.13 | 1.45 | 1.5 | 1.4 | 0.6 | 0 |
Note：" NA " expression cannot obtain numerical value.
The prognosis score value that obtain step 2.1 and threshold value, after comparative analysiss, obtain prognosis bona or prognosis malas.Than
As follows compared with analysis result criterion：If it is (i.e. pre- that the prognosis score value of described squamous cell carcinoma patients to be measured is less than or equal to threshold value
Score value is less than or equal to 0.597 afterwards), then judge this squamous cell carcinoma patients prognosis mala；If prognosis score value is more than threshold value (i.e. prognosis
Score value is more than 0.597), then judge this squamous cell carcinoma patients prognosis bona.
3rd, P5-ADC prognosis scale cancer method
A, with the lung tumor of squamous cell carcinoma patients to be measured be organized as detect sample, exempted from according to method described in above-mentioned steps 1
Epidemic disease histochemical staining and chemical score, obtain the expression score value of P5-ADC；
B, according to step 2.1 method, obtain prognosis score value；
C, the prognosis score value obtaining above-mentioned steps b, according to the method for step 2.2, obtain prognosis bona or prognosis malas.
Kaplan-Meier survival analysises are shown in 3 years overall survival of prognosis bona's group in scale cancer training group
96.2% (confidence interval be 75.7%-99.5%), and prognosis malas group overall survival is that 25.0% (confidence interval is
11.8%-40.7%) (P<B in 0.0001, Fig. 1).
4th, the checking of P5-ADC prognosis scale cancer method effectiveness
4.1st, with scale cancer test group as sample, the effectiveness of P5-ADC prognosis scale cancer method in step 3 is verified.
4.2nd, with CQ scale cancer group as sample, the effectiveness of P5-ADC prognosis scale cancer method in step 3 is carried out independently testing
Card.From during the data processing unlike above-mentioned 4.1, carrying out protein expression profile, only retain less than 2 disappearances
The patient of protein readings, to the expression score value assessing scale cancer related protein in CQ scale cancer group one by one, will express score value
It is normalized with scale cancer training group and scale cancer test group program, missing values are by this protein expression in BJ scale cancer group
Intermediate value substitute, then calculate the score value of each protein and the expression ratio of this protein meansigma methods of CQ scale cancer group,
Expression is with the log of expression ratio afterwards10(expression ratio) quantifies.In order to avoid in logarithm 0 appearance, all fractions
All add 0.01.
Kaplan-Meier survival analysises result shows, in scale cancer test group, prognosis bona's group 3 annual survival rates reach 72.7%
(confidence interval is 37.1%-90.3%), and prognosis malas group is 16.7% (confidence interval is 4.1%-36.5%), in advance
Well between group and prognosis malas group, Hazard ratio is 3.51 (confidence interval is 1.39-7.73) (in P=0.008, Fig. 1 afterwards
C)；Organize 3 annual survival rates in prognosis bona in CQ scale cancer group and reach 97.6% (confidence interval is 83.6%-99.7%), prognosis
Bad group of 3 annual survival rates reach 29.3% (confidence interval is 16.4%-43.4%), and Hazard ratio is 9.97 between the two, confidence
Interval is 4.46-17.99 (P<E in 0.001, Fig. 1).
Actual existence shape by the distribution of prognosis score value, prognosis prediction result, scale cancer characteristic spectrum and patient of BJ scale cancer group
State is summarized, and experimental result is shown in D in Fig. 1.Prognosis score value is shown with the comparative result of 3 years survival rates of patient, squama
Cancer characteristic spectrum can predict the prognosis situation of patient.
The actual survival condition of the Prognostic scoring system distribution, prognosis prediction result, scale cancer characteristic spectrum and patient of CQ scale cancer group
All similar to BJ scale cancer group (F in Fig. 1).The method of prognosis being further characterized by step 3 is pre- to squamous cell carcinoma patients prognosis
The effectiveness surveyed.
Can be used as an independent prognostic factor in order to analyze scale cancer characteristic spectrum further, we use single argument and changeable
Amount Cox regression analyses are to model and the existing clinical risk factor (including case classification, age, smoking and histology etc.)
Prognostic value be compared.Univariate analysiss result shows although this scale cancer characteristic spectrum and clinical scale distinguish patient
Prognosis be respectively provided with significant significant difference, but for the prediction of 3 years overall survival, scale cancer characteristic spectrum is one
Relatively more preferable prognostic factor；Multivariate regression analysis shows, eliminate case classification, the age, tumor size and
After smoking factor, scale cancer characteristic spectrum still can be used as an independent prognostic factor (table 4).
Cox proportional hazards analysis in the sample cluster of Chongqing for the table 4. lung squamous cancer model
Note：*Prognosis malas group is compared with prognosis bona's group；+As continuous variable
Embodiment 2, the further prognosis to the squamous cell carcinoma patients that TNM is classified for the P5-ADC prognosis scale cancer method
To the method for the further prognosis of the squamous cell carcinoma patients of TNM classification it is：Scale cancer to any rank being classified through TNM
Patient (as the patient of IB phase scale cancer), the method according to embodiment 1 obtains the expression score value of P5-ADC, then should
Expression score value, according to the method for embodiment 1 step 2.1, obtains prognosis score value；By each prognosis score value according to embodiment 1
The method of step 2.2, judges this squamous cell carcinoma patients prognosis bona or prognosis malas.
The sample of BJ group and CQ group is integrated and obtains total scale cancer sample, P5-ADC prognosis scale cancer method can be by total scale cancer sample
Each patient in this is further separated into prognosis malas group or prognosis bona's group (IB phase P on the basis of TNM classification<
0.0001；II phase P=0.0001；IIIA phase P=0.0008) (Fig. 2).Result shows, P5-ADC prognosis scale cancer
Method can carry out prognosis to squamous cell carcinoma patients on the basis of TNM classification further.
Claims (12)
1. be used for predicting the system of Lung Squamous Carcinoma Patients prognosis, include detecting EGFR, p 38 alpha, AKT1, SOX2 and
The system of this five kinds of protein expressions of E-cadherin.
2. according to claim 1 be used for predict Lung Squamous Carcinoma Patients prognosis system it is characterised in that：Described inspection
Survey EGFR, p 38 alpha, the system of this five kinds of protein expressions of AKT1, SOX2 and E-cadherin are included by immunity
Histochemical stain method detects the reagent needed for expression and/or the instrument of described five kinds of protein.
3. according to claim 1 or claim 2 prediction Lung Squamous Carcinoma Patients prognosis system it is characterised in that：Described use
System in prediction Lung Squamous Carcinoma Patients prognosis includes protein expression amount data handling system, described protein expression amount number
It is used for five kinds of protein expressions described in the detached lung squamous cell carcinoma cancers from Lung Squamous Carcinoma Patients to be predicted according to processing system
Amount is converted to the prognosis score value of described Lung Squamous Carcinoma Patients to be predicted, according to the prognosis score value of described Lung Squamous Carcinoma Patients to be predicted
Predict the prognosis of described Lung Squamous Carcinoma Patients to be predicted.
4. the detection EGFR described in claim 1 or 2, p 38 alpha, this five kinds of AKT1, SOX2 and E-cadherin
Application in the system of preparation prediction Lung Squamous Carcinoma Patients prognosis for the system of protein expression amount.
5. the detection EGFR described in claim 1 or 2, p 38 alpha, this five kinds of AKT1, SOX2 and E-cadherin
The system of protein expression amount and protein expression amount data handling system predict the system of Lung Squamous Carcinoma Patients prognosis in preparation
In application；
Described protein expression amount data handling system is the protein expression amount data handling system described in claim 3
1.
6. the application according to claim 4 or 5 it is characterised in that：Described detection EGFR, p 38 alpha, AKT1,
The system of this five kinds of protein expressions of SOX2 and E-cadherin includes measuring by Cell immunohistochemical staining method
The reagent needed for expression of described five kinds of protein and/or instrument.
7. a kind of method of prediction Lung Squamous Carcinoma Patients prognosis, including：C, detection are derived from dividing of Lung Squamous Carcinoma Patients to be predicted
From the EGFR of lung squamous cell carcinoma cancers sample, p 38 alpha, this five kinds of protein expressions of AKT1, SOX2 and E-cadherin；
D, described five kinds of protein expressions are converted to the prognosis score value of described Lung Squamous Carcinoma Patients to be predicted, according to described treat pre-
The prognosis score value surveying Lung Squamous Carcinoma Patients predicts the prognosis of described Lung Squamous Carcinoma Patients to be predicted.
8. method according to claim 7 it is characterised in that：Described five kinds of protein expressions are according to immunity
Histochemical stain method obtains.
9. the method according to claim 7 or 8 it is characterised in that：Described detached lung squamous cell carcinoma cancers sample
The sample prepared through formalin fix paraffin embedding from the detached lung squamous cell carcinoma cancers of described Lung Squamous Carcinoma Patients to be predicted
The frozen section of the detached lung squamous cell carcinoma cancers originally or from described Lung Squamous Carcinoma Patients to be predicted.
10. according to described method arbitrary in claim 7-9 it is characterised in that：According to described lung squamous cancer to be predicted
The prognosis score value of patient predicts that the prognosis of described Lung Squamous Carcinoma Patients to be predicted is included by Receiver operating curve
(ROC curve) determines diagnostic threshold, relatively the prognosis score value of described Lung Squamous Carcinoma Patients to be predicted and described diagnostic threshold
Size, complete Lung Squamous Carcinoma Patients prognosis prediction.
The application of 11.D1 and/or D2：
D1) EGFR, p 38 alpha, five kinds of protein of AKT1, SOX2 and E-cadherin are predicting lung squama as mark
Application in cancer patient's prognosis；
D2) EGFR, p 38 alpha, five kinds of protein of AKT1, SOX2 and E-cadherin are predicted in preparation as mark
Application in the product of Lung Squamous Carcinoma Patients prognosis.
A kind of 12. methods producing lung squamous cancer related protein characteristic spectrum, are derived from TNM I-III phase lung squama including detection
EGFR, p 38 alpha, five kinds of albumen of AKT1, SOX2 and E-cadherin in the detached lung squamous cell carcinoma cancers sample of cancer patient
The step of matter expression.
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